Epoxyeicosatrienoic acids (EETs) are signaling molecules that can act as short-range hormones, (i.e. they are autocrine and paracrine mediators) of the cardiovascular system and kidney. They produce vasorelaxation as well as anti-inflammatory and pro-fibrinolytic effects.
Hypertension and Related Conditions.
Cardiovascular disease afflicts 81 million of the 300 million people in the United States, and 75 million of these people have hypertension. CYP epoxygenase metabolites have biological actions that implicate them as important contributors to cardiovascular function and blood pressure control.
One of the first biological activities described for epoxyeicosatrienoic acids (EETs) was inhibition of renal tubular sodium reabsorption. Subsequently, EETs were determined to dilate blood vessels and were identified as endothelium-derived hyperpolarizing factors (EDHF). These biological actions are consistent with the idea that EETs would be eicosanoids that contribute to lowering of blood pressure and prevent salt-sensitive hypertension.
Altered levels of EETs may contribute to hypertension in humans. A single nucleotide polymorphism in a CYP epoxygenase gene is associated with hypertension. Experimental studies in rodents have also demonstrated hypertension in conditions where kidney CYP epoxygenase enzyme and/or EET levels were decreased. Increasing EET levels with 11,12-EET-SI, a 11,12-EET analog, improved renal afferent arteriolar function in vitro.
Currently, soluble epoxide hydrolase inhibitors (sEHI) are used in vivo to increase EET levels and this results in a generalized increase in 11,12-EET and 14,15-EET and to a lesser extent 8,9-EET. Recent in vivo studies have demonstrated that EET analogs lower blood pressure in hypertensive rats, and also ameliorate the metabolic syndrome phenotype in hemeoxygenase 2 deficient mice and prevent the adiposity-related vascular and renal damage. It does appear as if some of the EET agonists like NUDSA may also inhibit sEH and increase CYP2C epoxygenase expression. This type of combinational activity described for NUDSA could provide added beneficial effects. As a whole, these findings have generated interest in targeting the CYP epoxygenase pathway and EETs for the treatment of hypertension.
Even though EETs have actions on renal tubular transport and vascular function that are essential for blood pressure regulation it has become apparent that additional biological actions ascribed to EETs made them an excellent therapeutic target for other cardiovascular diseases. These additional activities demonstrated for EETs include inhibition of platelet aggregation and anti-inflammation. EETs also have been found to have effects on vascular migration and proliferation, including promoting angiogenesis. Thus, EETs have become a therapeutic target for end organ damage associated with cardiovascular diseases, cardiac ischemic injury, atherosclerosis, and stroke.
The therapeutic potential for EET agonists and sEHIs could extend beyond hypertension and cardiovascular diseases. Neural protection from ischemic injury has been attributed to sEHI actions on blood vessels and neurons. There is growing evidence that sEHIs provide protection from ischemic damage in the brain and heart through effects on apoptotic signaling cascades. EET agonists and sEHIs have also been demonstrated to modulate pain in various experimental animal models. Other possible therapeutic applications for EET agonists are sure to be discovered when these agents are tested in other disease models.
Accordingly, there is a need in the art for novel EET agonists that are active as therapeutic agents against hypertension and related cardiovascular and neural disease.
Drug-Induced Nephrotoxicity.
A common side-effect of many drugs used in the treatment of various conditions is nephrotoxicity. For instance, cisplatin, a platinum-based inorganic compound, is one of the most potent and widely used chemotherapy agents available to treat a variety of malignancies, including ovarian, lung, testicular and bladder cancers. Although, cisplatin is used as an important chemotherapy drug in the clinic, it has potentially lethal adverse effects. The most common of this adverse effect is nephrotoxicity (25-40% of cisplatin treated patients develop acute renal failure), which limits the safe and effective use of this widely used chemotherapeutic agent. The pathophysiology of cisplatin-induced nephrotoxicity involves enhanced oxidative stress, inflammation, increased endoplasmic reticulum (ER) stress and renal cell apoptosis.
EET is an important lipid mediator that exerts a number of biological actions including anti-inflammatory, anti-oxidative and anti-apoptotic activities. A numbers of studies demonstrated that with anti-inflammatory, anti-apoptotic and anti-oxidative activities, EET possess strong organ protective potential. For instance, increased EET bioavailability resulted from reduced conversion of EET to its less active form by soluble epoxide hydrolase (sEH) inhibitor provides kidney protection in a number of preclinical models of human diseases. These studies demonstrated that the kidney protective effect of EET was related to anti-inflammatory and anti-oxidative effects of EET. Indeed, there is strong evidence that EET have anti-inflammatory effects against acute and chronic inflammation. Apart from inflammation, EET also protect cells from apoptosis. Thus, there are strong evidences of EET's ability to protect organ by mechanisms involve its anti-inflammatory, anti-apoptotic and anti-oxidative activities.
However, it is known that endogenously produced EETs are chemically and metabolically labile. Also, rapid metabolism, low solubility and storage issue limit the therapeutic prospect of EET. As such considerable interest has arisen in developing strategies to enhance the bioavailability of EET. In this effort, attempts have been made to develop EET analogs that possess EET-mimetic activity along with several key features important for stability and bio-availability. Several of such EET analogs have demonstrated a number of biological activities including organ protection.
In the present study we have investigated the kidney protective effect of two newly developed orally active EET analogs in cisplatin-induced nephrotoxicity. We have demonstrated that EET analogs offered marked reno-protection during cisplatin administration and this effect was related to their anti-oxidative, anti-inflammatory, anti-ER stress and anti-apoptotic activities. We have further demonstrated that while protecting the kidney from the deleterious nephrotoxic effects of cisplatin, these EET analogs did not compromise cisplatin's chemotherapeutic effect.
Accordingly, there is a need in the art for novel EET analogs that are active as therapeutic agents against the deleterious nephrotoxic effects of cisplatin.